Anorectal dysfunction in multiple sclerosis patients: A pilot study on the effect of an individualized rehabilitation approach.

BACKGROUND: Anorectal dysfunction (ARD), especially bowel incontinence, frequently compromises the quality of life in multiple sclerosis (MS) patients. The effect of rehabilitation procedures has not been clearly established. OBJECTIVE: To determine the effect of an individualized rehabilitation approach on bowel incontinence and anorectal pressures. METHODS: MS patients with ARD underwent 6-months of individually targeted biofeedback rehabilitation. High resolution anorectal manometry (HRAM) and St. Mark's Fecal Incontinence Scores (SMIS) were completed prior to rehabilitation, after 10 weeks of supervised physiotherapy, and after 3 months of self-treatment. RESULTS: Ten patients (50%) completed the study. Repeated measures analysis of variance (ANOVA) demonstrated significant improvement in the SMIS questionnaire over time [14.00 baseline vs. 9.70 after supervised physiotherapy vs. 9.30 after self-treatment (p = 0.005)]. No significant improvements over time were noted in any HRAM readings: maximal pressure [49.85 mmHg baseline vs. 57.60 after supervised physiotherapy vs. 60.88 after self-treatment (p = 0.58)], pressure endurance [36.41 vs. 46.89 vs. 49.95 (p = 0.53)], resting pressure [55.83, vs 52.69 vs. 51.84 (p = 0.704)], or area under the curve [230.0 vs. 520.8 vs. 501.9 (p = 0.16)]. CONCLUSIONS: The proposed individualized rehabilitation program supports a positive overall effect on anorectal dysfunction in MS patients.

An anti-hair loss treatment in the management of mild androgenetic alopecia: Results from a large, international observational study.

Androgenic alopecia (AGA) is a common and chronic condition. It may impact self-esteem, self-image and quality of life. Benefit, tolerability, cosmetic acceptance and patient satisfaction are key to ensure good treatment outcome. Hair loss improvement and hair quality with AC5 (2,4-Diamino-Pyrimidine-N-Oxyde, arginine, 6-O glucose linoleate (SP94), piroctone olamine and Vichy mineralizing water) once daily was assessed in 527 subjects with mild AGA in an open-label, observational, international real-life study. After 3 months, investigators evaluated the impact of AC5 on hair loss, product satisfaction and asked subjects about local tolerance; subjects assessed hair growth and quality and satisfaction. Data from 357 subjects were evaluable for the benefit analysis; 59.9% of subjects were female; the mean age was 33.6±8.7 years. Duration of hair loss was 1.62±2.24 years. 71.3% of women had a Ludwig score of 1 and 40.8% of men had a Hamilton Norwood score of 2. At the end of study, hair loss was reduced in 89.0% of subjects; it was slightly higher in women (92.5%) than in men (83.8%). Subject satisfaction on a scale from 0 (not satisfied at all) to 10 (completely satisfied) was 7.9±1.7. Tolerance was rated good to very good by 98.6% of all subjects. In conclusion, AC5 reduces mild AGA in both men and women with a pleasant texture. AC5 was well tolerated and highly appreciated.

Activation mechanism of the heterodimeric GABA(B) receptor.

The GABA(B) receptor was the first heteromeric G-protein coupled receptor (GPCR) identified. Indeed, both GABA(B1) and GABA(B2) subunits appear necessary to get a functional GABA(B) receptor. Soon after the cloning of both subunits, it was demonstrated that GABA(B2) was required for GABA(B1) to reach the cell surface. However, even a mutated GABA(B1) able to reach the cell surface is not functional alone despite its ability to bind GABA(B) ligands. This clearly demonstrated that GABA(B2) is not only required for the correct trafficking of GABA(B1) but also for the correct functioning of the receptor. In the present review article, we will summarize our actual knowledge of the specific role of each subunit in ligand recognition, intramolecular transduction, G-protein activation and allosteric modulation. We will show that the GABA(B) receptor is an heterodimer (not an hetero-oligomer), that agonists bind in GABA(B1), whereas GABA(B2) controls agonist affinity and is responsible for G-protein coupling. Finally, we will show that the recently identified positive allosteric modulator CGP7930 acts as a direct activator of the heptahelical domain of GABA(B2), being therefore the first GABA(B2) ligand identified so far.

The second intracellular loop of metabotropic glutamate receptors recognizes C termini of G-protein alpha-subunits.

Heptahelical receptor coupling selectivity to G-proteins is controlled by a large contact area that involves several portions of the receptor and each subunit of the G-protein. In the G-protein alpha subunit, the C-terminal 5 residues, the N terminus, and the alpha N-beta 1 and alpha 4-alpha 5 loops play important roles. On the receptor side, both the second and third (i2 and i3) intracellular loops as well as the C-terminal tail probably contact these different regions of the G-protein. It is now accepted that the C terminus of the alpha subunit binds in a cavity formed by the i2 and i3 loops. Among the various G-protein-coupled receptors (GPCRs), class III receptors that include metabotropic glutamate (mGlu) receptors greatly differ from the rhodopsin-like GPCRs, but the contact zone between these receptors and the G-protein is less understood. The C terminus of the alpha subunit has been shown to play a pivotal role in the selective recognition of class III GPCRs. Indeed, the mGlu2 and mGlu4 and -8 receptors can discriminate between alpha subunits that differ at the level of their C-terminal end only (such as Gqo and Gqz). Here, we examine the role of the i2 loop of mGluRs in the selective recognition of this region of the alpha subunit. To that aim, we analyzed the coupling properties of mGlu2 and mGlu4 or -8 receptors and chimeras containing the i2 loop of the converse receptor to G-protein alpha subunits that only differ by their C termini (Gqo,Gqz, and their point mutants). Our data demonstrate that the central portion of the i2 loop is responsible for the selective recognition of the C-terminal end of the alpha subunit, especially the residue on position -4. These data are consistent with the proposal that the C-terminal end of the G-protein alpha subunit interacts with residues in a cavity formed by the i2 and i3 loops in class III GPCRs, as reported for class I GPCRs.

The intracellular loops of the GB2 subunit are crucial for G-protein coupling of the heteromeric gamma-aminobutyrate B receptor.

The gamma-aminobutyrate B (GABA(B)) receptor is the first discovered G-protein-coupled receptor (GPCR) that needs two subunits, GB1 and GB2, to form a functional receptor. The GB1 extracellular domain (ECD) binds GABA, and GB2 contains enough molecular determinants for G-protein activation. The precise role of the two subunits in G-protein coupling is investigated. GB1 and GB2 are structurally related to the metabotropic glutamate, Ca(2+)-sensing and other family 3 GPCRs in which the second (i2) as well as the third (i3) intracellular loop play important roles in G-protein coupling. Here, the role of the i2 loops of GB1 and GB2 in the GABA(B) receptor ability to activate G(alpha)-proteins is investigated. To that aim, the i2 loops were swapped between GB1 and GB2 heptahelical domains (HDs), either in the wild-type subunits or in the chimeric subunits GB1/2 that contain the ECD of GB1 and the HD of GB2. The effect of an additional mutation within the i3 loop of GB2 that prevents coupling of the heteromeric receptor was also examined. Combinations of interest were found to be correctly addressed at the cell surface and to assemble into heteromers. Taken together our data revealed the following new information on the G-protein coupling of the heteromeric GABA(B) receptor: 1) the i2 loop of GB2 within the GB2 HD is required for the heteromeric GABA(B) receptor to couple to G-proteins, whereas the i2 loop of GB1 is not; 2) the presence of the i2 loop of GB2 within the GB1 HD is not sufficient to allow coupling of GB1; 3) the GB2 HD activates the Gqi9 protein whether it is associated with the GB2 or GB1 ECD; 4) in the combination with two GB2 HDs, each is able to couple to G-proteins; and finally, 5) the use of mutations in i2, i3, or both within the GB2 HD brings evidence for the absence of domain swapping enabling the exchange of region including i2 and i3 between the subunits.